Program Abstract Since 1969, the Yale MD-PhD Program has provided excellent clinical and research training to highly- qualified applicants in order to meet its mission of training physician-scientists who will carry out basic, translational and clinical research that promotes the understanding and treatment of human disease. The Program has graduated 310 MD-PhD students, with the majority currently holding positions as trainees (21%) or faculty (61%) in clinical or basic science departments throughout the United States. These graduates have had a significant impact on biomedical and clinical research, as substantiated by the 2,290 papers published by 178 graduates between 1992-2013, and the high rates of research funding exhibited by faculty with academic appointments (almost 80% with one or more active grants since program inception). The Yale MD- PhD Program leverages the excellent and broad graduate training programs available in the Graduate School of Arts and Sciences, the School of Medicine, and the School of Epidemiology and Public Health to provide training opportunities in both traditional (e.g., Cell Biology, Immunobiology, Integrated Neurosciences) and newer (e.g. Biomedical Engineering, Stem Cell Biology, Medical Anthropology) areas of biological and biomedical science. At the same time, the Program has used internal and external review processes to implement initiatives that create a unique training experience for MD-PhD students. These include a curriculum that highlights the scientific basis of medical knowledge in the first years, and exposes students to excellent physician-scientist teachers and mentors from the start; a requirement for 6 months of medical clerkships prior to the start of thesis research, which allows students to have longitudinal clinical experiences that continue during their time in the lab; and programmatic activities that teach students communication, writing and leadership skills necessary for success in clinical and research realms. This application describes the growth of Yale University and Yale New Haven Hospital since the prior competitive renewal of this grant, and highlights the new training opportunities this has provided for our students. We discuss the new medical school curriculum and MD-PhD specific courses that will be implemented in the fall of 2015, which include a greater emphasis on training students in quantitative methods and biostatistics. We also provide details of oversight and mentoring programs that have contributed to an extremely low dropout rate (4%) among students during the past 10 years (2004-2013). Lastly, we provide a detailed plan for addressing new challenges and opportunities faced by the Program, including a commitment from Medical School leadership for increased programmatic support in this era of constrained NIH resources and a multipronged strategy to increase our ability to recruit, matriculate and train students from underrepresented or disadvantaged/disabled backgrounds to become successful physician-scientists, teachers and role models.